Natalizumab and PML in MS

Introduction

Natalizumab is an effective therapy for multiple sclerosis. In rare cases, it may be too potent in its ability to block ingress of T cells into the central nervous system. Natalizumab changes the ecology of the cell entry into the brain. This suggests new principles about multiple sclerosis therapy, T cell/endothelial cell interactions, central nervous system viral infections, and central nervous system immunology.

Questions addressed include:

The role of VLA-4 in adhesion of immune cells to endothelial cells in periphery and brain

Can PML be predicted, and can it be prevented by natalizumab washout in multiple sclerosis patients?

Natalizumab is a human IgG4k monoclonal antibody with short murine segments at the antigen recognition site. Natalizumab is derived by grafting short portions of low immunogenicity from the complementarity determining region of a potent murine anti-VLA-4 Ab to a human IgG4 chain. This immunoglobulin isotype does not bind complement and persists for a long time in the circulation. Natalizumab binds to the alpha-chain of VLA-4 glycoprotein (alpha4beta1 integrin) found on immune cell membranes. The antibody blocks VLA-4 interaction with VCAM-1 on endothelial cells. Related anti-VLA-4 antibodies also affect immune cell activation. After an impressively short trip from lab bench to bedside, natalizumab was approved by the FDA in 2004 for treatment of relapsing-remitting forms of multiple sclerosis. It is also effective in Crohn disease and possibly in rheumatoid arthritis.